Alkyl halides acetylide anion reactions with

The proton of terminal acetylenes is acidic (pKa= 25), thus they can be deprotonated to give acetylide anions which can undergo substitution reactions with alkyl halides, carbonyls, epoxides, etc. to give other acetylenes. 

As noted above, alkyne anions are very useful in Sn2 reactions with alkyl halides, and in acyl addition reactions to a carbonyl.46 Alkyl halides and sulfonate esters (tosylates and mesylates primarily) serve as electrophilic substrates for acetylides. A simple example is taken from Kaiser s synthesis of niphatoxin B, in which propargyl alcohol (36) is treated with butyllithium and then the OTHP derivative of 8-bromo-1-octanol to give a 47% yield of 37.48... 

There are two major reactions of enolates (1) displacement reactions with alkyl halides or other suitable electrophiles and (2) nucleophilic addition to carbonyl compounds. Reaction of 58 with butanal to give 59 and reaction of 61 with bromopentane to give 62 are simple examples of each process. Enolate anions function as carbon nucleophiles and their reactions are fundamentally the same as those discussed in Section 8.3.C for acetylides. Although there are interesting differences, treating an enolate anion as a carbon nucleophile is very reasonable. 

In the synthesis of propargylic alcohols, we saw the reaction of an alkynyl nucleophile (either the anion RC=CNa or the Grignard RC CMgBr, both prepared from the alkyne RC CH) with a carbonyl electrophile to give an alcohol product. Such acetylide-type nucleophiles will undergo Sn2 reactions with alkyl halides to give more substituted alkyne products. With this two-step sequence (deprotonation followed by alkylation), acetylene can be converted to a terminal alkyne, and a terminal alkyne can be converted to an internal alkyne. Because acetylide anions are strong bases, the alkyl halide used must be methyl or 1° otherwise, the E2 elimination is favored over the Sn2 substitution mechanism. 

Here too, a second alkylation can be made to take place yielding RC=CR or R C=CR. It should, however, be remembered that the above carbanions—particularly the acetylide anion (57)—are the anions of very weak acids, and are thus themselves strong bases, as well as powerful nucleophiles. They can thus induce elimination (p. 260) as well as displacement, and reaction with tertiary halides is often found to result in alkene formation to the exclusion of alkylation. 

Under the same conditions simple etiolates react vigorously with alkyl halides (which must be primary) to give mono- and polyalkylated products. The reactivity of the simple enolate is greater and cannot be controlled at room temperature. However, if the alkylation is carried out at low temperature, the reaction can be controlled and smooth monoalkylation of simple enolates can be achieved. The same is true for the alkylation of acetylide anions, which must be carried out at low temperature for successful alkylation. 

Finally, acetylide anions have been alkylated with propargyl halides to give excellent yields of dialkynes643,644. Similar reactions have been used in the synthesis of a wide variety of natural products including lactones and macrolides645,646 and leukotrienes647-651. With many halides, reaction with acetylide anions is not useful however, due to elimination side-reactions caused by the significant basicity of the carbanion. 

A Reaction of Acetylide Anions with Alkyl Halides... 

Reaction of acetylide anions with alkyl halides (11.11 A)... 

The major limitation to this reaction is that synthetically acceptable yields are obtained only with methyl halides and primary alkyl halides Acetylide anions are very basic much more basic than hydroxide for example and react with secondary and ter tiary alkyl halides by elimination... 

These compounds are sources of the nucleophilic anion RC=C and their reaction with primary alkyl halides provides an effective synthesis of alkynes (Section 9 6) The nucleophilicity of acetylide anions is also evident m their reactions with aldehydes and ketones which are entirely analogous to those of Grignard and organolithium reagents... 

The alkylation reaction is limited to the use of primary alkyl bromides and alkyl iodides because acetylide ions are sufficiently strong bases to cause dehydrohalogenation instead of substitution when they react with secondary and tertiary alkyl halides. For example, reaction of bromocyclohexane with propyne anion yields the elimination product cyclohexene rather than the substitution product 1-propynylcyclohexane. 

A wide array of substances can be prepared using nucleophilic substitution reactions. In fact, we ve already seen examples in previous chapters. The reaction of an acetylide anion with an alkyl halide (Section 8.8), for instance, is an Sn2 reaction in which the acetylide nucleophile replaces halide. 

Terminal alkynes are weakly acidic. The alkyne hydrogen can he removed by s strong base 9uch ae Na NH.. to yield nn a<%tylide anipn An acetylide anion ads as a nucleophile and can displace a halide ion from a primary alkyl halide in a n alkylation reaction. Acetylide anions are more stable iJian either alkyl anions or vinylic anions because their m ative charge is in a hybrid orbital with 50% s character, allowing the charge to be doser to the nucleus. 

Because acetylide anions are strong nucleophiles, the mechanism of nucleophilic substitution is S 2, and thus the reaction is fastest with CH3X and 1° alkyl halides. Terminal alkynes (Reaction [1]) or internal alkynes (Reaction [2]) can be prepared depending on the identity of the acetylide anion. 

Although nucleophilic substitution with acetylide anions is a very valuable carbon-carbon bondforming reaction, it has the same limitations as any Sn2 reaction. Steric hindrance around the leaving group causes 2° and 3° alkyl halides to undergo elimination by an E2 mechanism, as shown with 2-bromo-2-methylpropane. Thus, nucleophilic substitution with acetylide anions forms new carbon-carbon bonds in high yield only with unhindered CH3X and 1 ° alkyl halides. 

In each step, the base NHg removes an sp hybridized proton, and the resulting acetylide anion reacts as a nucleophile with an alkyl halide to yield an Sn2 product. The first two-step reaction sequence forms the terminal alkyne A by nucleophilic attack of the acetylide anion on CHaBr. 

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